The present invention relates to a coagulant plasma-protein solution obtained by adsorbing stabilized human plasma at least once with 20-40 mg of colloidal silicic acid per gram of plasma protein and separating the adsorbent from the adsorbate, to a method of manufacturing the solution, and to a pharmaceutical preparation containing the solution and intended for the intravenous treatment of complex disorders of the hemostatic system.
Treating patients suffering from hemostatic malfunctions with blood and blood components has been described in numerous publications [Bloom, A. L. & Thomas, D. P., Hemostasis and Thrombosis, Edinburgh, London, Melbourne, and New York, Churchill Livingstone, 1981, 472-90 and Lechner, K., "Rationelle Substitutionstherapie bei Gerinnungst/o/ rungen," Infusionstherapie 4, 5 (1980), 190-94, for example]. Intravascular malfunction is so manifold in the most various diseases that no uniform theoretical opinion has existed up to now as to the optimal methods of treatment. This is especially due to the practical impossibility of appropriate clinical studies because of the the multiplicity of the different syndromes. In practice, clinical experience has proven blood-component treatment to be successful. The commonest agents of this type are, apart from fresh blood, fresh plasma or fresh-frozen plasma, freeze-dried fresh plasma, platelet concentrate, cryoprecipitate, and the more or less highly purified clotting-factor concentrates like fibrinogen, antihemophilic globulin A (AHG or factor VIII), and the concentrates that contain clotting factor IX, sometimes in combination with factors II, VII, and X (PPSB concentrates).
The problematics of deciding as to the utilization of particular blood components or even particular inhibitors, heparin for instance, is evident in the clinical picture of consumption coagulopathy. Consumption coagulopathy (disseminated or generalized intravascular coagulation) is an acquired blood-clotting disorder characterized by increased consumption of plasma clotting factors and thrombocytes deriving from generalized intravascular coagulation [Lasch, H. G. et al, "Verbrauchskoagulopathien (Pathogenese und Therapie)," Folia haemat. (N.F.) 6, 325-30 (1961)]. Causative conditions that can be connected with consumption coagulopathy include bacterial shock, burns, carcinoma, leukemia, amniotic embolism, fat embolism, acidosis, hypoxemia, bacteriemia, virus diseases, organ transplants, and anaphylactic shock.
E. Lechler et al. point out ["Therapie bei Verbrauchskoagulopathie," Deutsche Medizinische Wochenschrift 100, 1, 24-25 (1975) that consumption coagulopathy leads to hemorrhagic diathesis and, by way of fibrin precipitation, to microcirculatory disorder accompanied by organic necrosis. Therapy should disrupt the intravascular coagulational process, specifically by treatment of the causative condition or pathogenic mechanism provoking the intravascular coagulation on the one hand and, on the other, by utilizing coagulation-inhibiting agents. This paper recommends heparin therapy for the treatment of consumption coagulopathy. G. Wolff ["Fresh frozen plasma: effects and side effects," Bibliotheca haemat. 46, 189-206 (1980)], on the other hand, is of the opinion that fresh frozen plasma is an extremely effective means for treating post-traumatic consumption coagulopathy, whereas treatment with heparin is by no means without danger and its basis is in no way recognized as decisive on a worldwide level. He states that heparin only replaces one kind of coagulation disorder with another and iatrogenic type.
H. Harke and S. Rahmen ["Haemostatic disorders in massive transfusion," Bibliotheca haemat. 46, 179-88 (1980)] demonstrated by means of various citations that patients' conditions are frequently not improved by the application of specific blood components but can sometimes even be worsened. They say that diffuse hemorrhagic tendencies based mainly on disruptions of the plasma and/or thrombocyte coagulation systems are among the postoperative complications most to be feared subsequent to massive transfusions. Characteristic changes in the plasma and thrombocyte system subsequent to massive transfusions should also indicate the significant part played by hemorrhagic shock in the occurrence of coagulation disorders. The authors also say that the risk of microembolism accompanied by more or less severe damage to organic perfusion seems to be unavoidable after massive transfusion, so that more attention should be paid from the aspect of organic insufficiency to the high lethality that follows massive transfusions of stored blood due to microembolism and the formation of microaggregates. One component that can lead to considerable deterioration in the clinical situation is fibrinogen in the plasmas, whether out-dated or fresh frozen and even when manufactured in accordance with the latest technical advances, administered to patients [cf. Koerner, K. et al., "Das tiefgefrorene Frischplasma in der Blutkomponententherapie: Herstellung--Qualit/a/ tskontrolle--Indikation," Infusionstherapie 8, 253-58 (May, 1981)]. The cited studies show that it is fibrin precipitation itself that leads to disruption of the microcirculation accompanied by organic necrosis.
German Pat. Nos. 1 617 319 and 1 617 335 describe methods of manufacturing lipoprotein-free, stable, and sterile sera. Blood serum or plasma is absorbed with 250-500 mg of colloidal silicic acid per gram of total protein at temperatures up to 50.degree. C., the silicic acid is separated, and the serum subjected to ultraviolet radiation and sterilized by filtration. The radiation is carried out under normal conditions--in the air.
European Pat. No. 14 333 describes a method of manufacturing several therapeutically useful plasma-protein preparations. Stabilized blood plasma is adsorbed on 50-400 mg of colloidal silicic acid per gram of plasma protein to harvest the fibrinogen and the fibrinogen-free plasma-protein solution obtained as an intermediate product is then further processed into, in addition to other preparations, a solution of serum proteins that will be stable under storage. The plasma-protein solution obtained as an intermediate product also contains some clotting factor. A citrated plasma treated with propiolactone and ultraviolet radiation (in the air) could be employed as a starting material.